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WHAT’S NEXT IN CANCER RESEARCH?

Immune checkpoint inhibition has been revolutionary in cancer care. However, the TME and the tumor itself work together to achieve immunosuppression and immune evasion to promote cancer growth.There may be opportunities to further understand and enhance the impact of checkpoint inhibitors.2-5,8,9

TGF-ꞵ engineers the TME to support and sustain tumor survival5-7

Why the tumor microenvironment matters

PD-L1 pathway signaling suppresses T-cell activation5,8

 

 

CAF, cancer-associated fibroblast; CPI, checkpoint inhibitor; DC, dendritic cell; EMT, epithelial-mesenchymal transition; MDSC, myeloid-derived suppressor cell; N2 TAN, TAN with N2 phenotype; NK, natural killer; ORR, overall response rate; PD-1, programmed death receptor-1; PD-L1, programmed death-ligand 1; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TGF-ꞵ, transforming growth factor-beta; TME, tumor microenvironment; Treg, regulatory T cell.

References: 1. Park J-I, Lee M-G, Cho K, et al. Transforming growth factor-β1 activates interleukin–6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-κB, JNK, and Ras signaling pathways. Oncogene. 2003;22:4314-4332. 2. Mpekris F, Voutouri C, Baish JW, et al. Combining microenvironment normalization strategies to improve cancer immunotherapy. Proc Natl Acad Sci U S A. 2020;117:3728-3737. 3. Van der Jeught K, Bialkowski L, Daszkiewicz L, et al. Targeting the tumor microenvironment to enhance antitumor immune responses. Oncotarget. 2015;6:1359-1381. 4. Zhang J, Endres S, Kobold S. Enhancing tumor T cell infiltration to enable cancer immunotherapy. Immunotherapy. 2019;11:201-213. 5. Allard B, Aspeslagh S, Garaud S, et al. Immuno-oncology-101: overview of major concepts and translational perspectives. Semin Cancer Biol. 2018;52(pt 2):1-11. 6. Liu T, Han C, Wang S, et al. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. 2019;12:86. doi:10.1186/s13045-019-0770-1. 7. Mariathasan S, Turley SJ, Nickles D, et al. TGFß attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544-548. 8. Tang H, Wang Y, Chlewicki LK, et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell. 2016;29:285-296. 9. Schmidt EV. Developing combination strategies using PD-1 checkpoint inhibitors to treat cancer. Semin Immunopathol. 2019;41:21-30.